Earnings Call Transcript - NTLA Q3 2024

Operator, Operator

Good morning and welcome to Intellia Therapeutics’ Third Quarter 2024 Financial Results Conference Call. My name is Drew and I will be your conference operator today. Following formal remarks, we will open the call for a question-and-answer session. This conference is being recorded at the company's request and will be available on the company's website after the call ends. As a reminder, all participants are currently in listen-only mode. I will now turn the conference over to Lina Li, Senior Director of Investor Relations and Corporate Communications at Intellia. Please proceed.

Lina Li, Senior Director of Investor Relations and Corporate Communications

Thank you, operator, and good morning, everyone. Welcome to Intellia Therapeutics third quarter 2024 earnings call. Earlier this morning, Intellia issued a press release outlining the company's progress this quarter, as well as topics for discussion on today's call. This release can be found on the Investors and Media section of Intellia's website at intelliatx.com. This call is being broadcast live and a replay will be archived on the company's website. At this time, I'd like to take a minute to remind listeners that during this call, Intellia management may make certain forward-looking statements and ask that you refer to our SEC filings available at sec.gov for discussion of potential risks and uncertainties. All information presented on this call is current as of today, and Intellia undertakes no duty to update this information unless required by law. Joining me from Intellia are John Leonard, Chief Executive Officer; David Lebwohl, Chief Medical Officer; Laura Sepp-Lorenzino, Chief Scientific Officer; and Ed Dulac, Chief Financial Officer. John will begin with recent business highlights, David will provide updates on our clinical pipeline progress, Laura will then provide R&D updates, and Ed will review our financials before we open the call for questions. With that, I will now turn the call over to John, our Chief Executive Officer.

John Leonard, Chief Executive Officer

Thank you, Lina. Good morning, everyone, and thank you all for joining us today. At Intellia, we are ushering in a new era of medicine. During the third quarter and more recent period, we've made substantial progress in our efforts to bring promising, highly differentiated, and potentially curative CRISPR-based gene editing treatments to patients. In October, at the American College of Allergy, Asthma and Immunology Annual Scientific Meeting, we presented unprecedented positive results from our Phase II study of NTLA-2002 for the treatment of Hereditary Angioedema. These results showed that a simple one-time infusion of NTLA-2002 offers patients the potential for a functional cure. For people living with HAE, current treatment options are limited to chronically administered prophylactic therapies to prevent or manage attacks, and the use of on-demand therapy to control breakthrough attacks. Because of this, available therapies place emphasis on attack rate reductions for their lifelong treatments. However, our market research is clear; patients want to lead a normal life, one that is free of attacks, free of chronic treatment, and free of mental burden around potential triggers and the loss of access to their therapies. The emerging profile for NTLA-2002 provides hope that a single intervention may lead to the complete elimination of angioedema attacks and remove the need for subsequent prophylaxis therapy for most patients; the opportunity to deliver such a profile will create significant value for patients and the healthcare system as a whole. We're extremely encouraged by our Phase II results, and we're actively screening patients in the Phase III HAELO study. The strong enthusiasm for NTLA-2002 from patients and our investigators strengthens our conviction that the Phase III will enroll rapidly, enabling us to submit a planned BLA in 2026. In addition, we're making excellent progress across our other late-stage trials. As announced this morning, the FDA cleared our IND application for MAGNITUDE-2, our Phase III trial of NEX-Z for patients with hereditary ATTR Amyloidosis with Polyneuropathy. We expect to initiate the study in the coming days. Since dosing our first cardiomyopathy patient in March, we continue to see strong momentum in our Phase III MAGNITUDE study, and enrollment is tracking ahead of our internal projections. With three active Phase III studies expected by year-end, we are leading the field of in vivo CRISPR-based medicines. Intellia is ushering in a new era of medicine with the prospect of functional cure for patients suffering from HAE and a treatment that may change the course of the disease for people with ATTR Amyloidosis. I'll now hand the call over to our Chief Medical Officer, David Lebwohl, who will provide an update on our clinical programs.

David Lebwohl, Chief Medical Officer

Thanks, John. I'll begin with NTLA-2002 in development for Hereditary Angioedema or HAE. As John noted, we presented Phase II data, which demonstrated that a single dose of NTLA-2002 could both eliminate attacks and eliminate the need for further treatment. In the 50-milligram arm, 8 of 11 patients had no attacks during the 16-week primary observation period after a single dose of NTLA-2002. These ground-breaking results highlight how NTLA-2002 has the potential to reset the standard of care for HAE. We are encouraged by the findings thus far from the post-primary observation period in the Phase II as well; the 8 patients who were attack-free in the 50-milligram cohort remain attack-free with no HAE directed therapy for a median of 8 months so far. Moreover, the 3 patients who are not yet attack-free achieved clinically meaningful attack rate reduction. Based on our Phase I observations, we expect these patients to show continued improvement or become attack-free as they have more time to adjust to their new normal. We are continuing to follow all patients and look forward to presenting longer follow-up data next year. With NTLA-2002, we believe we are creating a new standard for patient outcomes in HAE, where 12 out of 15 patients, or 80% of patients who received the 50-milligram dose in the Phase I/II study, appear functionally cured of their disease, i.e., patients were attack-free without the need for further treatment. This is unprecedented and suggests an emerging product profile that is unmatched by other HAE therapies, either currently approved or in development. Importantly, our market research indicates that NTLA-2002’s emerging product profile aligns directly with the needs and priorities of patients and physicians. As such, we expect broad interest and demand for NTLA-2002 that will drive rapid enrollment of our Phase III study and commercial uptake once approved. We are now actively screening patients in the HAELO Phase III study, a global, randomized, double-blind, placebo-controlled study. Importantly, our Phase III study will extend the primary observation period and look at the number of HAE attacks from weeks 5 through 28 as its primary endpoint. This is designed to provide a cleaner read into the drug's effects once TTR reduction has reached its steady state about a month after therapy. As previously guided, we expect to submit a BLA filing in 2026 from the 60-patient study. In summary, we believe NTLA-2002 is well positioned to be the first approved in vivo CRISPR gene editing treatment and a truly transformative one-time treatment for people living with HAE. Switching to NEX-Z, also known as NTLA-2001, in development for the treatment of ATTR Amyloidosis. This multi-system disease primarily manifests as either cardiomyopathy due to amyloid deposits in the heart, or polyneuropathy, through the progressive accumulation of protein deposits in the nervous system. We announced today that the U.S. FDA cleared our IND application to initiate a Phase III trial in patients with hereditary ATTR Amyloidosis with polyneuropathy. This marks our fourth consecutive IND clearance within 30 days of submission for in vivo therapies we have developed, an unparalleled regulatory track record in the field of gene editing, and testament to our high standard for drug development. Our MAGNITUDE-2 Phase III trial is an international randomized, double-blind, placebo-controlled study. 50 patients will be enrolled and randomized one-to-one to receive a single 55-milligram infusion of NEX-Z or placebo. Patients randomized to the placebo arm will be eligible for optional crossover to receive NEX-Z. The primary endpoints are the change from baseline in mNIS+7 at month 18, and serum TTR at day 29. In polyneuropathy, there is a positive correlation between greater TTR protein reduction and improved clinical benefit. To date, no other agent approved or in clinical development has demonstrated consistent, deep, and durable TTR reduction like NEX-Z, which gives us tremendous confidence in our ability to positively impact patient outcomes in the MAGNITUDE-2 study. We expect to initiate the study at ex-U.S. sites in the coming days. Simultaneously, the rapid enrollment of the MAGNITUDE trial in patients with cardiomyopathy continues to track ahead of our internal projections based on strong patient and physician interest. In total, we are actively enrolling patients at over 60 sites and have received regulatory clearance in more than 20 countries for the Phase III study. Findings in a recent publication of a competitor's clinical data in ATTRCM indicate that there is a major opportunity to improve patients' clinical outcomes beyond what current therapies provide. In our ongoing Phase I study, we demonstrated that all patients for cardiomyopathy achieved rapid, deep, and durable TTR reduction with NEX-Z, more consistent and greater mean reductions than that reported with TTR silencers. As such, our early clinical data suggests NEX-Z could significantly reduce total TTR exposures, which in turn might provide greater clinical benefit for patients. Next Saturday, November 16, we will be presenting new findings from the ongoing Phase I study as a late-breaking oral presentation at the American Heart Association scientific sessions. On the occasion of AHA’s 100th Anniversary, we will be presenting data at the opening session titled 'Celebrating A Century of Cardiovascular Science From Prevention To Treatment To Cure'. These data will provide insights into the emerging clinical profile of NEX-Z and the hypothesis that greater TTR reduction leads to better clinical outcomes. The update will include data from all 36 patients within the cardiomyopathy arm, including important measures of clinical and functional benefit. This includes safety, reduction of TTR, and disease progression markers such as NT-proBNP, troponin, six-minute walk test at month 12 compared to baseline. We look forward to reviewing these data on an investor webcast taking place that same day, where we will also provide an update on the polyneuropathy arm. I'll now hand the call over to Laura, our Chief Scientific Officer, who will provide updates on the 3001 program and our R&D efforts.

Laura Sepp-Lorenzino, Chief Scientific Officer

Thank you, David. Good morning, everyone. We're advancing our science beyond in vivo knockout therapies and into our first in vivo gene insertion programs in the clinic. NTLA-3001 is our first wholly owned in vivo gene insertion program for alpha-1 antitrypsin deficiency associated lung disease. It is designed to precisely insert the wild-type SERPINA1 gene, which encodes the alpha-1 antitrypsin protein. In previous presentations, we provided non-human primate data, showing the ability to produce fully functional alpha-1 protein at normal levels after a single dose. Notably, these normal levels of alpha-1 protein were durable through 2 years of follow-up in the completed study. We expect to dose the first patient in the Phase I/II study of NTLA-3001 by year-end. If we're able to translate what we have seen in non-human primates to humans, we believe this will be a major step forward for alpha-1 patients and the field of gene editing. Assuming success, it would unlock a whole new category of diseases which require a gain of function that we could pursue with our modular insertion platform. In parallel, we're continuing to advance our toolbox of novel gene editing and delivery technologies to extend the reach of CRISPR-based gene editing for in vivo and ex vivo therapeutic applications. This includes advancing gene editing programs in five different tissues outside the liver, either independently or in collaboration with partners. We're proud of all the recent progress and look forward to providing more updates as we advance our platform and pipeline. I’ll now hand over the call to Ed, our Chief Financial Officer, who will provide an update on our financial results as of the third quarter 2024.

Ed Dulac, Chief Financial Officer

Thank you, Laura, and good morning, everyone. Intellia continues to maintain a solid balance sheet that allows us to execute on our pipeline and platform. Our cash, cash equivalents, and marketable securities were approximately $944.7 million as of September 30, 2024, compared to $1 billion as of December 31, 2023. The decrease was driven by cash used to fund operations of approximately $335 million. The decrease was offset in part by $176.9 million of net equity proceeds from the company's after-market program, $47 million of collaborator reimbursements including a one-time $30 million payment received in April related to the company's technology collaboration with Regeneron, $37.2 million of interest income, and $6.5 million in proceeds from employee-based stock plans. Our collaboration revenue was $9.1 million during the third quarter of 2024, compared to $12 million during the third quarter of 2023. The $2.9 million decrease was mainly driven by a reduction in revenue related to the AvenCell license and collaboration agreement. R&D expenses were $123.4 million during the third quarter of 2024, compared to $113.7 million during the third quarter of 2023. The $9.7 million increase was primarily driven by the advancement of our lead programs. Stock-based compensation included in R&D expense was $24.2 million for the third quarter. G&A expenses were $30.5 million during the third quarter of 2024, compared to $29.4 million during the third quarter of 2023. The $1.1 million increase was primarily related to stock-based compensation. Stock-based compensation included within G&A expense was $15.4 million for the third quarter of 2024. Finally, we expect our cash balance to fund our operating plans until late 2026.

John Leonard, Chief Executive Officer

Thanks, Ed. In conclusion, Intellia continues to deliver on the promise of gene edits, and we look forward to presenting the NEX-Z Phase I update next week at AHA. With that, we will now open the call for your questions. To do our best to address as many questions as possible, we will only be able to take one question per caller. Operator, you may now open the call for Q&A.

Operator, Operator

The first question comes from Rick Bienkowski with Cantor Fitzgerald.

Rick Bienkowski, Analyst

I was just hoping to get more color on the enrollment into MAGNITUDE-1. Just looking at the clinical trial record on clinicaltrials.gov, the estimated primary completion is listed at December 2027. So, could you just walk me through the assumptions there for the pace of enrollment, given that the primary endpoint is event-driven?

John Leonard, Chief Executive Officer

Thanks for the question, Rick. As we've said, you can use the HAELO study as a really good proxy with similar assumptions. You know that the study has 765 patients, we have global sites activated, and the final sites are being activated as we speak here. So as we said in our comments here, we're enrolling ahead of our projections, and as we get further insight, there may be an opportunity to update that down the road. But in the meanwhile, things are progressing very, very well.

Operator, Operator

The next question comes from Alec Stranahan with Bank of America.

Unidentified Analyst, Analyst

This is Matthew on for Alec. Thanks for taking our question. Just one quick one for us. As you think about extending into later-stage clinical trials, just thinking about your capital allocation priorities, given you have a lot going on in the pipeline, and sort of how you're thinking about in vivo versus ex vivo going forward.

John Leonard, Chief Executive Officer

So, maybe Ed can address that, and we'll follow up as necessary.

Ed Dulac, Chief Financial Officer

Yes, thanks for the question. We exited the third quarter about $945 million in cash. And as we look at our 2 or 3-year plan, I think we've laid out at JPMorgan earlier this year, 3-year priorities; strategic priorities through 2026. And so as I look at the company today, we clearly have a focus on the 3 Phase III studies which will be up and running before the end of the year, and that's clearly our focus. We do have some exciting programs related to NTLA-3001, our first gene insertion program, which is an important proof-of-concept for us, as well as sort of burgeoning opportunities as well. And then we've been very prominent in just investing across the platform. So, I look at our existing cash burn at roughly, you know, $100 million over the last couple of quarters. As a reasonable estimate that should go up, but I feel like we have a very conservative plan in place; one that takes our existing cash balance and gets us well into the fourth quarter of 2026.

Operator, Operator

The next question comes from Yanan Zhu with Wells Fargo Securities.

Yanan Zhu, Analyst

First, congratulations on receiving FDA clearance to conduct the Phase III study in ATTR polyneuropathy. I noticed two aspects of the trial design that stood out. One is that it is a placebo-controlled study rather than an active arm-controlled study. The other is the small sample size, with only 50 patients, which is less than half the size of the silencer studies. Could you elaborate on this study design and its implications? Additionally, will patients in either arm be permitted to receive a silencer or other active treatments during the study? Thank you.

John Leonard, Chief Executive Officer

Thanks for the question, Yanan. First of all, it's important to note that the effect size of TTR reduction is very, very large in patients with polyneuropathy, that's been established. We have pretty good insight as to the effects as a function of TTR reduction. And as we've shared elsewhere, our TTR reduction is profound and we expect that to continue into this patient population in Phase III. A placebo-controlled trial is possible based on our agreement with the FDA and other regulatory agents. It will give us a very solid readout on the performance and safety of the drug. And by carrying it outside the United States where many of these other therapies are not currently available, it allows the study to be enrolled promptly, and we'll be in a position to share the data when we have it. And David, you can speak to any other details that you think are pertinent to that study or silencers.

David Lebwohl, Chief Medical Officer

Thank you, John. I think what you're seeing in this small study is a great collaboration with the FDA as we talk to them about the best way to go forward. All other drugs have been approved with placebo-controlled study; so that makes a lot of sense as well for our drug. And again, silencers are not available in the country where the studies are being conducted, so patients will not be receiving silencers.

Operator, Operator

The next question comes from Mani Foroohar with Leerink.

Unidentified Analyst, Analyst

Hi, good morning. This is CJ on for Mani. My question is regarding the Phase III HAELO study, I just noticed that patients are randomized 2-to-1 there versus 1-to-1 in MAGNITUDE. So, I was just wondering if you thought this 2-to-1 enrollment was thought to accelerate patient enrollment in the study? Thank you.

John Leonard, Chief Executive Officer

David, do you want to speak to the randomization scheme?

David Lebwohl, Chief Medical Officer

Yes. The advantage of a 2-to-1 randomization is mainly for the patients themselves. It's appealing to them because they have a two-thirds chance of starting on the active drug immediately. Additionally, all these patients will have the option to crossover if they choose to at the end of the primary observation period, which makes it even more attractive. Given these factors, we expect very rapid enrollment, similar to what we experienced in the Phase II study. With the 2-to-1 setup, we’ll have more data on the active arm for the BLA submission expected in 2026.

Operator, Operator

The next question comes from Costas deLoris with BMO Capital Markets.

Unidentified Analyst, Analyst

Good morning, everyone. Thanks for taking our question and congrats on the progress. One question from us on the AATP program. Given that the gene that you inserted isn't under the control of the natural promoter and under infection, patients need about 2x to 3x more AAT protein. Can you remind us how do you ensure that these additional AAT protein is there during infections? Thank you.

John Leonard, Chief Executive Officer

We are excited about the alpha-1 program based on the preclinical ALB, where the natural transgene is regulated by the albumin promoter. In non-human primates, we have achieved normal levels of the protein. I wouldn't anticipate this to vary significantly in response to infection since it is controlled by the albumin promoter. Our priority has been to normalize the protein levels, as this is the primary deficiency in patients with the disease. We believe this will be the key factor in determining the success of the product.

Operator, Operator

The next question comes from Joseph Thome with TD Cowen.

Joseph Thome, Analyst

Good morning. Congrats on the progress, and thank you for taking my question. Maybe just on the MAGNITUDE-2 study. As the TTR serum reduction is going to be a day 29 read and the MS is 18 months; are you able to take a look at serum TTR ahead of that 18-month time point while maintaining some sort of blind or should we anticipate both of those readouts coming at once? And then secondly, on any submission for PN; how much does the submission in PN depend on also success in MAGNITUDE-1 for CM or are these completely uncoupled? Thank you.

John Leonard, Chief Executive Officer

Maybe I can address that and David can fill in blanks. The two programs, polyneuropathy and cardiomyopathy, are independent of each other, and they're determined by the study designs in each of those particular indications. We’ve talked earlier on the call here about the cardiomyopathy program and how to think about that. The polyneuropathy program was pointed out; we'll have an 18-month observation period that's set in time, sort of a landmark design. But the two are independent of each other. We would expect that safety will be supplementary from each of the programs as data accumulates, but in terms of the efficacy read, they're entirely independent. The study is blinded, and we will not be in a position where we be sharing data prematurely before the complete data readout. So don't look for TTR. And then the ultimate clinical outcomes, it will be the full set of data as it becomes available. David, if you have anything to add to that; be my guest.

David Lebwohl, Chief Medical Officer

Just to add to the observation we've seen in our data, all patients have a significant reduction in TTR. While we won't be analyzing that data, our experience indicates that all patients will achieve a rapid and substantial reduction in TTR, and that appears to be maintained, likely permanently, based on what we know so far, especially over the two-year period. We will see that during the unblinding, as John mentioned, and we have a good understanding of what to expect from the data.

Operator, Operator

The next question comes from Gena Wang with Barclays.

Unidentified Analyst, Analyst

Hi, it's Tony on for Gena. So on ATTR, can you remind us of your assumptions for silencer drop-in rate? And any strategies to address this if it ends up being higher than expected?

John Leonard, Chief Executive Officer

David, do you want to speak to the silencer drop-in rate?

David Lebwohl, Chief Medical Officer

Yes. We have figured that into our trial. We haven't given the exact way that will happen. We should mention, we think it's less likely now that we've seen the Helios data, that there will be much drop-in. What we've seen is that there is some addition to TTR to the drop-in in that trial, but probably not enough to justify payers to pay for both drugs together. So what we expect to see is that patients will continue on the study; they possibly may switch to the drug if payers allow that. But even that switch, we don't think will have any effect on our primary endpoint.

Operator, Operator

The next question comes from Maury Raycroft with Jefferies.

Maury Raycroft, Analyst

Congrats on the progress, and thanks for taking my question. Just wondering if you could just talk more about how you're setting expectations for the AHA update for biomarkers in relationship or correlation to functional capacity? I'm wondering if you'll show individual patient data, potentially cardiac remodeling or imaging data as well.

John Leonard, Chief Executive Officer

I think I can start with that question, and David can fill in some additional information. As we said in our comments, we're very enthusiastic about sharing the data at the upcoming AHA meeting, and we're honored to be featured in the opening session of the meeting which is something that is addressing the next century of cardiac therapies; we’re very excited to be a part of that. As we've long said, we'll share biomarker data, functional data, and clinical information on these patients. And in terms of how we think about that meaning of that information; first, we're excited about what we see because it relates for the first time the extent of the TTR reduction that we're achieving with those particular readouts. And we think it will yield real insights into how we think about the MAGNITUDE study, and how we expect that the drug to perform in that particular study. David, if you want to share any other comments?

David Lebwohl, Chief Medical Officer

Yes. As you see the data from November 16, in the recent Phase III, the active groups continued to show worsening in these biomarkers. While BNP continues to rise, the six-minute walk test continues to decline; although they perform better than the placebo, they are still deteriorating overall. Therefore, it's important to note our data, which provides robust evidence of the impact of deep TTR reductions on clinical outcomes. This is particularly significant since 50% of our patients are class 3, compared to about 10% in other studies. Furthermore, 31% of our patients have variant disease, characterized as a very aggressive form of ATTRCM, while this is only around 10% to 12% in other studies. You will see data for all 36 patients in the study, as they have all completed one year, and we will present the data comparing their baseline to one year.

Operator, Operator

The next question comes from Ryan Forcep with Guggenheim.

Unidentified Analyst, Analyst

What factors do you think are the major contributors to enrollment being ahead of schedule in the MAGNITUDE ATTRCM study? And do you think these factors apply to MAGNITUDE-2 for PM?

John Leonard, Chief Executive Officer

What investigators tell us is, they've been extremely excited with the extent of the TTR reduction and the safety profile that they see with the drug to the state. We've seen a confirmation with competitor programs that lowering TTR is meaningful for patients, and the deep, consistent, and enduring reductions that we've achieved with the drug thus far, I think is really excited treating physicians around the world. We would anticipate that this will apply also to the MAGNITUDE study, and recall that in many of these countries this kind of therapy is not available for patients, generally speaking, and we know that there's great enthusiasm with all the sites that we've spoken to.

Operator, Operator

The next question comes from Dae Gon Ha with Stifel.

Dae Gon Ha, Analyst

Good morning. Thanks for taking our questions, and congrats on the progress. A question on AETD; just thinking about the Phase I that's going to embark by the end of the year. If you can comment on any flexibility in that trial protocol to include any liver disease patients, I know that was supposed to be more of a 2003 purview, but given the biology and the potential, say facilitation of polymer excretion from the cells once you have more M-protein? Just wondering if you can add in a little bit of that Sentinel cohort, if you will, just to see the benefit there. Thanks so much.

John Leonard, Chief Executive Officer

David, any process including liver disease in the 3001 trial?

David Lebwohl, Chief Medical Officer

Yes. These patients will not have any significant liver disease. Patients with liver disease are best treated by reducing the mutant protein, and increasing alpha-1 anti-trypsin would also be beneficial for them. However, without our capability to reduce the Z-protein, we believe we are not fully addressing their needs.

John Leonard, Chief Executive Officer

Just to add, we’re taking an extended approach to going after alpha-1. And in addition to 3001, which we think will teach us a lot about the insertion approach for alpha-1 disease and reads to a multiplicity of other diseases for which insertion may be the path forward. We're also bringing forward a gene writing program that would address not only the lung but also the liver.

Operator, Operator

The next question comes from Luca Issi with RBC.

Unidentified Analyst, Analyst

Thanks so much for taking our question. This is Lisa on to Luca. Congrats on all the progress here team and getting the IND cleared for TTR polyneuropathy. Just one question on the study, I know the primary endpoint is mNIS+7 at 18 months. However, I believe an nyeloma is able to file on just 9 months of follow-up. So I'm just curious if the 18-month endpoint was mostly needed to satisfy European regulators or did the FDA also request the longer follow-up? Any color here would be helpful. Thanks so much.

John Leonard, Chief Executive Officer

David, any comments on the 18 months versus a different follow-up time?

David Lebwohl, Chief Medical Officer

Yes. We determined that 18 months was the best duration to truly observe the full benefits of the drug based on the trials. While it wasn't mandated by regulators, it was our own choice to proceed with that timeline.

Operator, Operator

The next question comes from Salveen Richter with Goldman Sachs.

Unidentified Analyst, Analyst

Hi, this is Mark on for Salveen. First, congrats on the quarter, and thank you for taking our questions. The recently presented Phase II data from NTLA-2002 in HAE; can you discuss the data in the context of read-through to the recently initiated Phase III HAELO study? And any takeaways that you're applying to HAELO?

John Leonard, Chief Executive Officer

Well, thanks for the question. And I think it's really important to step back and consider what we've actually presented for NTLA-2002 thus far. If you take the 50 milligram doses from both the Phase I and Phase II studies, we now have reported on 12 of 15 patients who have achieved what we're considering a functional cure. That means patients following a single dose and no other therapy thereafter, have no attacks; that is unique in this space, it's a new category of response, it is achieved, to our knowledge, only with NTLA-2002 in this class of drugs. We expect that similar outstanding results will come from our Phase III trial. The study design is similar, with the exception that we have an even longer follow-up period to see further insights into how patients would respond with even a longer observation period. What we've seen in our Phase I study is that while many patients get to a functional cure fairly quickly, there are some patients that reach that only with some additional time. So we expect that we'll have very favorable results in our Phase III program, and look forward to sharing that as we go forward.

Operator, Operator

The next question comes from Myles Minter with William Blair.

Unidentified Analyst, Analyst

This is John on for Myles. Thanks so much for taking our question. So for NTLA-3001, I was just wondering if you could give us any idea of how many patients you are looking to dose before reporting initial data? And what kind of target are you looking for serum AAT levels in those lower dose cohorts?

John Leonard, Chief Executive Officer

Thanks for the question. We've had a principle that we've applied since the outset with all of the clinical work that we've done here, which is that we report data when it's meaningful, consistent and interpretable, and we'll apply that same standard here. Obviously, we're looking for a biomarker here which is readily measured; that's the production of the native protein, the wild type. And we've said from the outset that our objective here is to normalize the levels of that protein, and that will be the basis for determining the success of the project.

Operator, Operator

The next question comes from June Lee with Truist Securities.

Unidentified Analyst, Analyst

Hi, good morning. This is Medi on for June, and thanks for taking our question. Given your great progress on in vivo programs that you have, any color on your future plans for using gene writing technology is really appreciated. For example, do you plan to use it for in vivo or is this more for your ex vivo programs?

John Leonard, Chief Executive Officer

Thanks for the question. It really goes to the heart of the strategy of the company, where it's a three-pronged approach. We start with a platform that has a complete set of tools, not only on the editing side but also on the delivery side, so that as we look at any particular editing problem, we're in a position to choose what we think will be the best tool for the particular problem; and we apply those tools in both the in vivo and the ex vivo setting. We think that there are conditions for which gene writing is well suited; I don't think that's universally true. We think that there are certain instances, especially in the ex vivo setting, where base editing is useful, where one is going to multiplex. And then, of course, as we've shown with our ongoing Phase III programs, archetypal CRISPR, as exemplified by NTLA-2001 and NTLA-2002 has profoundly successful results in terms of achieving the editing objectives that we're going after. So you know, in short, we'll look at the particular programs and the editing that they need, and apply gene writing to that. One of the places where we think it's well suited is as an adjunct to our alpha-1 program, and that would be the first place where I would expect to see it.

Operator, Operator

The next question comes from Jay Olson with Oppenheimer.

Jay Olson, Analyst

Congrats on all the progress, and thank you for taking the question. How are you thinking about the ex-U.S. opportunity and strategy for NTLA-2002? Are you interested in partnering the program ex-U.S.? Thank you.

John Leonard, Chief Executive Officer

Behind that is the assumption that there's a substantial commercial opportunity around the world, certainly in developed markets, and we see that starting in the U.S. and going beyond the U.S. into Europe and perhaps beyond that. Our current plans are to be in a position to launch the drug ourselves. As we evaluate partnerships, we consider what they can bring to the table to extend our own reach. And as appropriate as we learn more about that, we would share that strategy as we go forward.

Operator, Operator

The next question comes from Brian Cheng with JPMorgan.

Unidentified Analyst, Analyst

This is Sean on for Brian. Just speaking on the AETD program, just curious about your thoughts on the back of some of the RNA editing data from your peers. How do you view NTLA-3001’s differentiation versus theirs?

John Leonard, Chief Executive Officer

As we've mentioned before, we believe that the key factor for success in treating the pulmonary aspects of the disease is attaining levels of wild-type protein that are high, essentially normal. So far, we are the only company we know of that has demonstrated this in a non-human primate setting. This is what we aim to assess in our Phase I study, to see if we can achieve similar protein levels in humans. Naturally, we are keeping an eye on the competition, as there are other programs developing, but it's still very early in the process. We will observe how effectively others are able to deliver their technologies and produce the normal protein over time.

Operator, Operator

The next question comes from Silvan Tuerkcan with Citizens JMP.

Silvan Tuerkcan, Analyst

Just a quick question, and I may have missed this, but for MAGNITUDE-2, congratulations on the IND. When do we plan to initiate this trial in the U.S.? Additionally, what will be the eventual split of patients enrolled in this trial between the U.S. and other countries?

John Leonard, Chief Executive Officer

Thanks for the question. We've tried to make it clear elsewhere that the study will be done outside the United States. It's there where one can readily conduct a placebo-controlled trial; standards of care otherwise for these patients are similar around the world. We've worked on developing this protocol with the Food and Drug Administration in the United States, and they will accept the program coming from patients that are studied outside the United States.

Operator, Operator

The next question comes from William Pickering with Bernstein.

William Pickering, Analyst

For the AHD program, do you have any plans to expand this study beyond the New Zealand site? And is it a reasonable base case that we would see data in 2025?

John Leonard, Chief Executive Officer

David, do you want to speak to any other sites besides New Zealand?

David Lebwohl, Chief Medical Officer

Yes. We will be having other sites, and we'll put them on clincaltrials.gov as they come up. I should say it is possible that we'll have data, reasonable to think we have data in 2025.

Operator, Operator

The next question comes from Andy Chen with Wolf Research.

Unidentified Analyst, Analyst

Hi, Brandon on for Andy. So we know docs are excited about your ATTR therapy, but can you please compare the excitement relative to their excitement for stabilizers and silencers? So let's say, you achieved similar efficacy on endpoints based on feedback now, are docs much more likely to use gene editing compared to a silencer, for example? Any safety concerns about using gene editing in a very old population?

John Leonard, Chief Executive Officer

David's on the front-line talking to investigators. Can you speak to the enthusiasm for investigators that we work with who, by the way, many of them have worked with silencers already; so they are in a position to be thinking about both of those compounds.

David Lebwohl, Chief Medical Officer

Yes, thank you, John. You've heard our belief for several years that achieving deeper reductions in TTR will yield better results. Our drug is also quicker in reaching low levels compared to silencers and maintains those low levels continuously, unlike periodic drug infusions. Given our success in achieving these low levels, we have received significant enthusiasm from physicians who believe this could be superior to silencers. We aim to confirm this in Phase III, and this feedback from investigators is why we think enrollment is progressing rapidly. There have been no safety concerns raised in older populations, and the drug has been well tolerated by all patients, including those in class 3 and very ill patients. All participants were able to receive the full dose of the drug as part of their therapy in the trial.

John Leonard, Chief Executive Officer

Maybe something to add is that we now have over 3 years of follow-up in our earliest dose patients, and the excellent safety profile that we reported in the early days has continued. We think many of the questions that surrounded gene editing are being addressed as these programs enroll. I think another thing to keep in mind with respect to patients who are older, which typifies the wild-type patient population; these patients live for a long time, and you can look at the recently reported results and see that there is high levels of survival, years after the patients have been dosed. I think that speaks importantly to the role of these agents; what they can do for these patients, the evolving care of them, and ultimately a pharmacoeconomic argument for treating patients like this, who should derive the full benefit of the therapy. One other thing with respect to older patients, it's common to think of TTR cardiomyopathy as a heritable disease. In fact, in most cases, it's a disease of aging. Over 90% of the patients who suffer from the disease have wild-type protein, and you can see that in the Phase III trials that have been reported. So unfortunately, we're making many more of these patients annually as the population ages, and so it's not correct to think about it as a typical sort of genetic disease.

Operator, Operator

The next question comes from Whitney Ichem with Canaccord Genuity.

Unidentified Analyst, Analyst

This is Juan on for Whitney. Just trying to understand the rationale for the 2001 polyneuropathy IND, given that Phase III will be run ex-U.S. Any color you can provide on that? Just want to make sure we're not missing any nuance here.

John Leonard, Chief Executive Officer

Why do we have an IND; to do the study outside the United States.

David Lebwohl, Chief Medical Officer

Yes. The reason is that when you plan a BLA in the United States, it's a good idea to get agreement with the FDA on the design of that study. And that's what we've obtained with this IND; they agree to the study you're seeing presented today, and this will go forward to a BLA in the U.S., as well as around the world.

Operator, Operator

This concludes our question-and-answer session. I would like to turn the conference back over to Lina Li for any closing remarks.

Lina Li, Senior Director of Investor Relations and Corporate Communications

Thanks, Drew, and thanks everyone for your question today. We appreciate all of your continued support, and look forward to connecting with everyone again after the AHA presentation on Saturday, November 16. Have a great day.

Operator, Operator

The conference has concluded. Thank you for attending. You may now disconnect your line.